Alpha adrenergic receptors are plasma membrane receptors which are located in the peripheral and central nervous systems throughout the body. They are members of a diverse family of structurally related receptors which contain seven putative helical domains and transduce signals by coupling to guanine nucleotide binding proteins (G-proteins). These receptors are important for controlling many physiological functions and, thus, have been important targets for drug development during the past 40 years. Examples of alpha adrenergic drugs include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and p-aminoclonidine (for glaucoma). However, most of these drugs produce undesirable side effects which may be due to the their interactions with other receptor subtypes. For example, clonidine is a well known centrally acting antihypertensive agent. However, it also produces untoward side effects such as analgesia, sedation, bradycardia and dry mouth which may be due to its lack of selectivity for a specific receptor subtype, i.e. xcex12 receptor.
Alpha adrenoceptors were originally proposed to have only two(alpha and beta) subtypes (Berthelsen, S.; Pethinger W. Life Sci. 1977, 21, 595). However, modern molecular biological and pharmacological techniques have led to the identification of at least 6 subtypes (xcex11a, xcex11b, xcex12a, xcex12b and xcex12c) of the adrenoceptors (Bylund, D. B., Trends Pharmacol. Sci. 1988, 9, 356; Weinshank et al, U.S. Pat. No. 5,053,337, issued Oct. 1, 1991; Bard et al, International Publication No. WO 94/08040, published Apr. 14, 1994).
Among many other therapeutic indications, xcex12 receptors are believed to modulate pain and behavioral depression by regulating locus coeruleus firing. In addition, xcex12 receptors are well known to be involved in effects on blood pressure, heart rate, vasoconstriction and glaucoma. However, it is not known which therapeutic. indications are controlled by each of these subtypes.
The effects of alpha-2 receptor agonists on analgesia, anesthesia and sedation have been well documented for past 10 years (Pertovaara, A., Progress in Neurobiology, 1993, 40, 691). For example, systematic administration of clonidine has been shown to produce antinociception in various species including human patients in addition to its well known sedative effects. Intrathecal and epidural administration of clonidine has also proved effective in producing antinociception. Another alpha-2 agonist, Medetomidine, which has better alpha-2/alpha-1 selectivity and is more potent at alpha-2 receptors than clonidine, has been extensively studied for its antinociception effect. In the spinally-initiated heat-induced tail flick test in rats, systematic administration of medetomidine produced a dose-dependent antinociception which could be totally reversed by alpha-2 receptor antagonists, atipamazole or idazoxan. Experimental studies of medetomidine on pain sensitivity in humans also indicated that this agent is very effective on ischemic pains, even though effective drug doses were high enough to produce a sedation and considerable decrease in blood pressure.
Effects of alpha-2 receptor agonists in anaesthetic practice have also been investigated. The sedative effect of alpha-2 agonists is regarded as good component of premedication. Another beneficial effect of alpha-2 agonists in anaesthetic practice is their ability to potentiate the anaesthetic action of other agents and to reduce anaesthetic requirements of other drugs during surgery. Studies shows that premedication with 5 xcexcg kxe2x88x921 of oral clonidine administration reduced fentanyl requirements for induction and intubation by 45% in patient undergoing aortocoronary bypass surgery (Ghingnone, M, et al, Anesthesiology 1986, 64, 36).
This invention is directed to novel benzimidazole derivatives which are selective for cloned human alpha 2 receptors. This invention is also related to uses of these compounds as analgesic, sedative and anaesthetic agents. In addition, this invention includes using such compounds for lowering intraocular pressure, and treatment of migraine, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemia, spasticity, diarrhea, nasal decongestion. Furthermore the compounds may be useful as cognition enhancers.
This invention provides compounds having the structure: 
wherein each of R1, R2, R3 and R9 is independently H; straight chain or branched, substituted or unsubstituted C1-C7 alkyl, C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; acyl, phenyl, substituted phenyl, or heteroaryl; wherein each dashed line represents a single bond or a double bond with the proviso that if R1 is. present, R3 is absent and there is a double bond between N at position 3 and C at position 2 and a single bond between C at position 2 and N at position 1 and if R3 is present, R1 is absent and there is a double bond between N at position 1 and C at position 2 and a single bond between C at position 2 and N at position 3; wherein each of R4, R5 and R6 is independently H, F, Cl, Br, I; straight chain or branched, substituted or unsubstituted C1-C7 alkyl, C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl, xe2x80x94OH, xe2x80x94OR7, xe2x80x94CN, xe2x80x94COR7, xe2x80x94CO2R7, xe2x80x94CON (R7)2, xe2x80x94OCOR7, xe2x80x94SR7, xe2x80x94N (R7)2, xe2x80x94NR7COR7, xe2x80x94(CH2)nOR7, xe2x80x94( CH2)nN (R7)2, xe2x80x94(CH2)nNR7COR7, wherein n is an integer from 1 to 4; and wherein each of R7 and R8 is independently H; straight chain or branched, substituted or unsubstituted C1-C7 alkyl, C2-C7 alkenyl or alkynyl; phenyl or substituted phenyl.
These compounds are selective for cloned human alpha 2 receptors and are useful as analgesic, sedative or anaesthetic agents.
The present invention is directed to compounds having the structure: 
where each of R1, R2, R3 and R9 is independently H; straight chain or branched, substituted or unsubstituted C1-C7 alkyl, C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; acyl, phenyl, substituted phenyl, or heteroaryl; where each dashed line represents a single bond or a double bond with the proviso that if R1 is present, R3 is absent and there is a double bond between N at position 3 and C at position 2 and a single bond between C at position 2 and N at position 1 and if R3 is present, R1 is absent and there is a double bond between N at position 1 and C at position 2 and a single bond between C at position 2 and N at position 3; where each of R4, R5 and R6 is independently H, F, Cl, Br, I; straight chain or branched, substituted or unsubstituted C1-C7 alkyl, C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl, xe2x80x94OH, xe2x80x94OR7, xe2x80x94CN, xe2x80x94COR7, xe2x80x94CO2R7, xe2x80x94CON(R7)2, xe2x80x94OCOR7, xe2x80x94SR7, xe2x80x94N(R7)2, xe2x80x94NR7COR7, xe2x80x94(CH2)nOR7, xe2x80x94(CH2)nN(R7)2, xe2x80x94(CH2)nNR7COR7, where n is an integer from 1 to 4; and where each of R7 and R8 is independently H; straight chain or branched, substituted or unsubstituted C1-C7 alkyl, C2-C7 alkenyl or alkynyl; phenyl or substituted phenyl.
The compound may have the following preferred structure: 
where each of R1, R2, R3, R4 and R6 is defined above.
In addition, the invention further describes compounds having the following structures: 
Acid salts of the compounds described above may be also be prepared. The acid salts may be but are not limited to the following HCl, HBr, HI, H2SO4, CH3COOH, CF3COOH, HNO3, CF3SO3H, CH3SO3H, C4H4O4, HO2CCHxe2x95x90CHCO2H, HO2CCHxe2x95x90CHCO2H, HO2CCH (OH) CH (OH) CO2H.
The invention also describes a pharmaceutical composition comprising a therapeutically effective amount of the compounds described above and a pharmaceutically acceptable carrier.
The invention further describes a method for treating an alpha-2 adrenergic receptor associated disorder or alleviating pain in a subject which comprises administering to the subject an amount of a compound having the structure: 
where each of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is defined above.
The invention describes a method for treating an alpha-2 adrenergic receptor associated disorder or alleviating pain in a subject which comprises administering to the subject an amount of a compound having the structure: 
where each of R1, R2, R3, R4 and R6 is defined above.
The invention describes a method for alleviating pain in a subject which comprises administering to the subject an amount of a compound having the structure: 
The method described above may be used to treat alpha-2 adrenergic receptor associated disorders such as hypertension, rheumatoid arthritis, ischemia, spasticity, glaucoma, migraines, alcohol withdrawal, drug addiction, diarrhea, or nasal congestion.
The compounds may be administered to a subject suffering from an alpha-2 adrenergic receptor associated disorder. The effective quantity of the compounds described above is from about 0.01 mg/dose to about 100 mg/dose and preferably from about 0.1 mg/dose to about 20 mg/dose. Such dose levels will depend upon the half-life of the compounds see for example Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeutics,xe2x80x9d Eighth Edition, 1990, Pergamon Press, pages 3-32.
Administration for the above compounds may be by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, ophthalmic, subcutaneous, intratumoral, intradermal, and parenteral.
The present invention also provides compounds useful for preparing a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier. The composition may contain between 0.1 mg and 500 mg of any of the compounds, and may be constituted in any form suitable for the mode of administration selected.
The compounds may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical is additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intraperitoneal or subcutaneous injection.
Sterile solutions can also be administered intravenously.
The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration, include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Four general synthetic methods were used to synthesize the compounds described herein. These methods are illustrated in Reaction Schemes 1-4.
The compounds herein have been prepared using synthetic sequences shown in Schemes 1-4. C-4 halogen substituted 5-aminobenzimidazoles were obtained from commercially available 5-nitrobenzimidazole by the sequence of hydrogenation and halogenation. C-4 alkyl substituted analogs were prepared in a similar reaction sequence in which alkyl group was incorporated using a Grignard reaction (Scheme 1). Reaction of 5-aminobenzimidazole with 2-imidazoline-2-sulfonic acid (ISA) which was obtained from 2-imidazolinethione (Gluchowski, C. U.S. Pat. No. 5,130,441) provides access to 2-aminoimidazolines in high yield (45-95%). C-2 substituted 5-nitrobenzimidazoles were prepared by condensation of 4-nitro-1,2-phenylenediamine with corresponding acids (Scheme 2). C-2 substituted 5-nitrobenzimidazoles were subjected to the same reaction sequence as Scheme 1 to provide the desired final product. Reaction of alkyl halides with 5-nitrobenzimidazole in the presence of NaH provided both N-1 and N-3 substituted benzimidazoles (Scheme 3). The reaction mixtures were subjected to hydrogenation (H2/Pd-C) to produce the corresponding amines, which were separated on column chromatography. Each amine was subjected to the reaction sequence described in Scheme 1 to provide the final product.
Preparation of C-7 substituted benzimidazoles is illustrated in Scheme 4. Halogenation of 2,4-dinitroaniline provided 6-halogen substituted anilines, which were subjected to hydrogenation and condensation in formic acid to provide 7-halosubstituted 5-aminobenzimidazoles. These intermediates were coupled to ISA to provide the desired products. C-7 alkyl substituted benzimidazoles were prepared using a similar sequence of reactions. Accordingly, 6-bromo-2,4-dinitroaniline was converted to 6-alkyl or aryl substituted analogs by the Pd(II) catalyzed coupling reaction. Conversion of alkyl substituted anilines to benzimidazoles was carried out in same reaction sequences described in Scheme 2. 